The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient[unreadable] supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated,[unreadable] irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of the Project[unreadable] is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will[unreadable] be accomplished by utilizing an integrative approach including cellular and molecular studies as well as[unreadable] integrative whole animal physiology. This Project is based on a model of repetitive stunning in the swine,[unreadable] developed in the current funding period, that reproduces the chronic myocardial dysfunction with maintained[unreadable] viability that characterizes the human hibernating myocardium. We show in the Preliminary Data that the well[unreadable] defined cardioprotective mechanisms attributed to the first and second window of preconditioning are not[unreadable] activated in the model of repetitive stunning. Rather, in this model, cardiac protection results from the[unreadable] activation of a different gene/protein program of cell survival, and also from the regulation of specific[unreadable] intracellular pathways, including autophagy. Accordingly, this may represent a third window of protection.[unreadable] The goal of this proposal is to better define the mechanisms of cardioprotection activated in this model of[unreadable] repetitive stunning, to determine their durability, to compare those mechanisms with those activated during[unreadable] preconditioning, and to determine whether the repetition of ischemia extends this cardioprotection to the[unreadable] remote, normal myocardium. Importantly, the swine model of repetitive stunning resembles pathophysiology[unreadable] in humans more closely than rodents, lacks preformed coronary collateral vessels, and the heart is[unreadable] sufficiently large to provide measurements of regional function, blood flow, biochemistry, molecular biology[unreadable] and pathology from the same animals in both the ischemic zone and a contralateral, remote, non-ischemic[unreadable] zone. This project is tied closely to the other projects and cores, as well as to the major themes of the[unreadable] Program Project: 1)Mechanisms of myocardial ischemia and reperfusion; 2)Molecular signaling;[unreadable] 3)Myocardial protection and cell survival vs. cell death; 4)lntegrative cardiovascular research. This project is[unreadable] linked closely to Project 1, which also studies the chronically instrumented swine model, but in Project 1 the[unreadable] model is one of regional cardiac denervation. Indeed, several of the aims are shared by Projects 1 and 2,[unreadable] using two different models. It will be critical to compare the cellular/molecular alterations in Projects 1 and 2[unreadable] to derive an understanding of the differences between the second and potentially, third window of protection.[unreadable] Project 2 interacts with Project 3 in terms of molecular signaling and mechanisms of apoptosis, and with[unreadable] Project 4 particularly related to H11 kinase and its role in the protection afforded by chronic, repetitive[unreadable] stunning. Project 2 also utilizes all of the Cores.